About the Yadavalli Lab


Bacteria must quickly sense and adapt to a variety of challenging environments. Stress response networks that are meant to protect the bacterial cells are also increasingly found to contribute to the rise of antimicrobial resistance. Antimicrobial resistance is an alarming problem of the present and future. Understanding the biochemical and regulatory pathways that underlie this resistance is of utmost importance to tackle the growing threat of untreatable multidrug-resistant bacterial infections. In our previous work, we found that treating E. coli with sublethal concentrations of an antimicrobial peptide (C18G) causes cells to filament. This filamentation is dependent on the PhoQ/PhoP two-component signaling network, important for survival in response to signals such as low magnesium, acidic pH, osmotic upshift, and the presence of cationic antimicrobial peptides, and regulates virulence in E. coli, Salmonella, and related bacteria. This work demonstrates that the block in cell division is not due to cell wall/membrane damage induced by the antimicrobial peptide, but instead the result of a high stimulus through this two-component system. Filamentation is mediated by an enzyme, QueE, which participates in the biosynthesis of a tRNA modification called queuosine (Q). We are currently investigating the details of the mechanism of cell division inhibition by QueE in response to antimicrobial peptide stress. 


In the past decade, numerous small proteins have been discovered in both eukaryotes (<100 amino acids) and prokaryotes (<50 amino acids). It is becoming increasingly clear that this class of proteins is important for the regulation of cell physiology under stress conditions. Uncovering the identities and functions of small proteins will expand our understanding of this under-explored class of regulatory molecules in the cell. We have a very limited understanding of most aspects of small protein biology. To expand our understanding of the mechanistic and physiological roles of small proteins, we are developing biochemical tools to a) identify cellular targets of these small proteins, and b) study roles of small protein regulators in stress response to specific signals. Our most recent research on small proteins was focused on a small membrane peptide MgrB, which is an inhibitor of PhoQ sensor kinase. We analyzed the molecular details of MgrB-PhoQ interactions using a combination of biochemical and biophysical approaches including beta-galactosidase reporter gene assays, single-cell fluorescence measurements, bacterial two-hybrid tests, as well as fluorescence resonance energy transfer. We identified a group of specific functionally important residues in the transmembrane as well as periplasmic regions of this protein. Interestingly, despite the small length of MgrB, a majority of amino acids are dispensable based on alanine-scanning mutagenesis. In addition to the aforementioned techniques, we are using high-throughput transcriptomic and proteomic tools to decipher the roles of small protein regulators.

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